Being one of the most predominant leukemia-predisposing syndromes, Down syndrome (DS) may provide valuable insight into the mechanisms underlying leukemogenesis in the general population. Individuals with DS face a 10-50X increased risk of AMLs and ALLs, and a 500X increased incidence of AMKL. Unique to AMKL are specific mutations in the GATA1 gene, but it is unknown why individuals with DS are at an increased risk of AML or ALL. I have shown that hematopoietic stem and progenitor cells (HSPCs) from the Dp16 mouse model of DS show significantly impaired self-renewal in culture, demonstrating precocious differentiation. These defects coincide with reduced in-vivo competitiveness of DS HSPCs relative to WT cells. Our lab has developed an evolutionary biology-based model we term Adaptive Oncogenesis, that attempts to explain observed fitness advantages of oncogenically initiated stem cells in irradiated, old, or stressed niches through relative fitness advantages or disadvantages. The general hypothesis is that when cells of the hematopoietic system are young and healthy (and in healthy niches), they are at a peak fitness level, which favors the status quo (i.e. few oncogenic mutations could be adaptive). Highly fit stem cells essentially outcompete oncogenically initiated cells. When the hematopoietic system sustains damage like radiation or aging, the overall fitness of the HSPCs decline, and certain oncogenic mutations may restore the fitness of individual cells and allow them to expand and progress to the stage of a leukemia. The overall idea behind this proposal is that, like an irradiated or aged hematopoietic system, the HSPCs in DS are less fit than WT HSPCs, and therefore certain oncogenic mutations may be adaptive in DS HSPC pools. Through the Dp16 mouse model of DS, the first goal of this project is to understand the mechanism behind the age-dependent functional decline in DS HSPCs, as a restoration of peak function may inhibit leukemogenesis. The second goal is to determine if certain oncogenic mutations confer a relative fitness advantage to a cell in the DS hematopoietic system. The research proposed here will fits well with the goal of the National Cancer Institute to support training in the fieldof cancer research.